Open Access Gateway
Med Princ Pract 2005;14:49–57
(DOI:10.1159/000086184)

Molecular Mechanisms of Organelle Biogenesis and Related Metabolic Diseases

Dhaunsi G.S.
Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait
email Corresponding Author


 goto top of outline Key Words

  • Organelle biogenesis
  • Mitochondria
  • Lysosomes
  • Peroxisomes
  • Metabolic diseases

 goto top of outline Abstract

Organelle biogenesis is regulated by transcriptional networks that modulate expression of specific genes encoding organellar proteins. Structural and functional specificity of organelles requires not only the transcription of specific genes and translation of resulting mRNAs, but also the transfer of encoded polypeptides to their site of function through signaling peptides. A defect in targeting of proteins to their subcellular site of function may not necessarily prevent biogenesis of the organelle, but would definitely lead to formation of a defective organelle with respect to that specific function. Several metabolic diseases are associated with dysfunction or defects in organelle biogenesis; among these, peroxisome biogenesis disorders, mitochondrial biogenesis defects and lysosomal storage disorders are an extensively studied group of genetic diseases where biogenesis of the organelle is compromised either due to a defect in assembly of the organelle itself or impaired import of matrix proteins into the organelle. Recent advances in biochemical and molecular aspects of biogenesis of subcellular organelles have not only unraveled the mechanisms for organization of cellular networks, but have also provided new insights into the development of metabolic diseases that are caused by disruption of organelle biogenesis. This article reviews the molecular mechanisms of biogenesis of mitochondria, lysosomes and peroxisomes in relation to the metabolic diseases of genetic or nongenetic origin.

Copyright © 2005 S. Karger AG, Basel


 goto top of outline References
  1. Nunnari J, Walter P: Regulation of organelle biogenesis. Cell 1996;84:389–394.
  2. Warren G, Wickner W: Organelle inheritance. Cell 1996;84:395–400.
  3. Hill C, Treisman R: Transcriptional regulation by extracellular signals: Mechanisms and specificity. Cell 1995;80:199–211.
  4. Palade G: Membrane biogenesis: An overview. Methods Enzymol 1983;96:29–55.
  5. Anderson S, Bankier AT, Barrel BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, et al: Sequence and organization of the human mitochondrial genome. Nature 1981;290:457–465.
  6. Marin-Garcia J, Goldenthal MJ: Mitochondrial biogenesis defects and neuromuscular disorders. Pediatr Neurol 2000;22:122–129.
  7. Lazarow PB, Fujiki Y: Biogenesis of peroxisomes. Annu Rev Cell Biol 1986;1:489–530.

    External Resources

  8. Lazarow PB, Moser HW: Disorders of peroxisome biogenesis; in Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995, pp 2287–2324.
  9. Tager JM: Inborn errors of cellular organelles: An overview. J Inherit Metab Dis 1987;10 (Suppl1):3–10.
  10. Walter P, Johnson AE: Signal sequence recognition and protein targeting to the endoplasmic reticulum membrane. Annu Rev Cell Biol 1994;10:87–119.
  11. Ryan KR, Jensen RE: Protein translocation across mitochondrial membranes: What a long, strange trip it is. Cell 1995;83:517–519.
  12. Senior AE: ATP synthesis by oxidative phosphorylation. Physiol Rev 1988;68:177–230.
  13. Orrenius S: Mitochondrial regulation of apoptotic cell death. Toxicol Lett 2004;149:19–23.
  14. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD: The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science 1997;275:1132–1136.
  15. Chang DD, Clayton DA: Priming of human mitochondrial DNA replication occurs at the light-strand promoter. Proc Natl Acad Sci USA 1985;82:351–355.
  16. Fisher RP, Clayton DA: Purification and characterization of human mitochondrial transcription factor 1. Mol Cell Biol 1988;8:3496–3509.
  17. Virbasius JV, Scarpulla RC: Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: A potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci USA 1994;91:1309–1313.
  18. Scarpulla R: Nuclear control of respiratory chain expression in mammalian cells. J Bioenerg Biomembr 1997;29:109–119.
  19. Gugneja S, Scarpulla RC: Serine phosphorylation within a concise amino-terminal domain in nuclear respiratory factor 1 enhances DNA binding. J Biol Chem 1997;272:18732–18739.
  20. Gugnega S, Vibasius CA, Scarpulla RC: Nuclear respiratory factors 1 and 2 utilize similar glutamine-containing clusters of hydrophobic residues to activate transcription. Mol Cell Biol 1996;16:5708–5716.
  21. Clayton DA: Transcription and replication of animal mitochondrial DNAs. Int Rev Cytol 1992;141:217–232.
  22. Lenka N, Vijayasarathy C, Mullick J, Avadhani NG: Structural organization and transcription regulation of nuclear genes encoding the mammalian cytochrome c oxidase complex. Prog Nucleic Acid Res Mol Biol 1998;61:309–344.
  23. Berg JM: Sp1 and the subfamily of zinc finger proteins with guanine-rich binding sites. Proc Natl Acad Sci USA 1992;89:11109–11110.
  24. Phillipsen S, Suske G: A tale of three fingers: The family of mammalian Sp/XKLF transcription factors. Nucleic Acids Res 1999;27:2991–3000.
  25. Huang RP, Fan Y, Ni Z, Mercola D, Adamson ED: Reciprocal modulation between Sp1 and Egr-1. J Cell Biochem 1997;66:489–499.
  26. Silverman ES, Khachigian LM, Lindner V, Williams AJ, Collins T: Inducible PDGF A-chain transcription in smooth muscle cells is mediated by Egr-1 displacement of Sp1 and Sp3. Am J Physiol 1997;273:H1415–H1426.
  27. Chacinska A, Rehling P: Moving proteins from the cytosol into mitochondria. Biochem Soc Trans 2004;32:774–776.
  28. Komiya T, Sakaguchi M, Mihara K: Cytoplasmic chaperones determine the targeting pathway of precursor proteins to mitochondria. EMBO J 1996;15:399–407.
  29. Komiya T, Rospert S, Schatz G, Mihara K: Binding of mitochondrial precursor proteins to the cytoplasmic domains of the import receptors Tom70 and Tom20 is determined by cytoplasmic chaperones. EMBO J 1997;16:4267–4275.
  30. Eilers M, Endo T, Schatz G: Adriamycin, a drug interacting with acidic phospholipids, blocks import of precursor proteins by isolated yeast mitochondria. J Biol Chem 1989;264:2945–2950.
  31. Pfanner N, Douglas MG, Endo T, Hoogenraad NJ, Jensen RE, Meijer M, Neupert W, Schatz G, Schmitz UK, Shore GC: Uniform nomenclature for the protein transport machinery of the mitochondrial membranes. Trends Biochem Sci 1996;21:51–52.
  32. Pfanner N, Meijer M: Mitochondrial biogenesis: The Tom and Tim machine. Curr Biol 1997;7:R100–R103.
  33. Schatz G: The protein import system of mitochondria. J Biol Chem 1996:271:31763–31766.
  34. Rehling P, Brandner K, Pfanner N: Mitochondrial import and the twin-pore translocase. Nat Rev Mol Cell Biol 2004;5:519–530.
  35. Larsson N, Clayton DA: Molecular genetic aspects of human mitochondrial disorders. Annu Rev Genet 1995;29:151–178.
  36. Schon EA, Bonilla E, DiMauro S: Mitochondrial DNA mutations and pathogenesis. J Bioenerg Biomembr 1997;29:131–149.
  37. Corona P, Lamantea E, Greco M: Novel heteroplasmic mtDNA mutation in a family with heterogenous clinical presentations. Ann Neurol 2002;51:118–122.
  38. Santorelli FM, Mak SC, El-Schahawi M: Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA(Lys) gene (G8363A). Am J Hum Genet 1996;58:933–939.
  39. Holt IJ, Harding AE, Morgan-Hughes JA: Deletions of mtDNA in patients with mitochondrial myopathies. Nature 1988;331:717–719.
  40. Larsson N, Oldfors A, Holme E, Clayton DA: Low levels of mitochondrial transcription factor A in mitochondrial DNA depletion. Biochem Biophys Res Commun 1994;200:1374–1381.
  41. Poulton J, Morten K, Freeman-Emmerson C, Potter C, Sewry C, Dubowitz V, Kidd H, Stephenson J, Whitehouse W, Hansen FJ, Parisi M, Brown G: Deficiency of the human mitochondrial transcription factor h-mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion. Hum Mol Genet 1994;3:1763–1769.
  42. Goffart S, Wiesner RJ: Regulation and co-ordination of nuclear gene expression during mitochondrial biogenesis. Exp Physiol 2003;88:33–40.
  43. Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, Bracale R, Valero A, Francolini M, Moncada S, Carruba MO: Mitochondrial biogenesis in mammals: The role of endogenous nitric oxide. Science 2003;299:896–899.
  44. Leary SC, Shoubridge EA: Mitochondrial biogenesis: Which part of ‘NO’ do we understand? Bioessays 2003;25:538–541.
  45. Griffiths G: What’s special about secretory lysosomes? Semin Cell Dev Biol 2002;13:279–84.
  46. de Duve C: The lysosome concept; in de Reuck AVS, Cameron MP (eds): Lysosomes. Boston, Little Brown, 1963, pp 1–35.
  47. Eskelinen EL, Tanaka Y, Saftig P: At the acidic edge: Emerging functions for lysosomal membrane proteins. Trends Cell Biol 2003;13:137–145.
  48. Orlow SJ: Melanosomes are specialized members of the lysosomal lineage of organelles. J Invest Dermatol 1995;105:3–7.
  49. Griffiths GM, Argon Y: Structure and biogenesis of lytic granules. Curr Top Microbiol Immunol 1995;198:39–58.
  50. Spritz RA: Multi-organellar disorders of pigmentation: Tied up in traffic. Clin Genet 1999;55:309–317.
  51. Meikle PJ, Hopwood JJ: Lysosomal storage disorders: Emerging therapeutic options require early diagnosis. Eur J Pediatr 2003;162(Suppl 1):S34–S37.

    External Resources

  52. Mullins C, Bonifacino JS: The molecular machinery for lysosome biogenesis. Bioessays 2001;23:333–343.
  53. Murphy RF: Maturation models for endosome and lysosome biogenesis. Trends Cell Biol 1991;1:77–82.
  54. Storrie B, Desjardins M: The biogenesis of lysosomes: Is it a kiss and run, continous fusion and fission process? Bioessays 1996;18:895–903.
  55. Dell’Angelica EC, Mullins C, Caplan S, Bonifacino JS: Lysosome-related organelles. FASEB J 2000;14:1265–1278.
  56. Luzio JP, Rous BA, Bright NA, Pryor PR, Mullock BM, Piper RC: Lysosome-endosome fusion and lysosome biogenesis. J Cell Sci 2000;113:1515–1524.
  57. Hunzikar W, Geuze HJ: Intracellular trafficking of lysosomal membrane proteins. Bioessays 1996;18:379–389.
  58. Bonifacino JS, Dell’Angelica EC: Molecular bases for the recognition of tyrosine based sorting signals. J Cell Biol 1999;145:923–926.
  59. Kirchhausen T: Adaptors for clathrin-mediated traffic. Annu Rev Cell Dev Biol 1999;15:705–732.
  60. Diaz E, Pfeffer SR: YIP47: A cargo selection device for mannose-6-phosphate receptor trafficking. Cell 1998;93:433–443.
  61. Wan L, Molloy SS, Thomas L, Liu G, Xiang Y, Rybak SL, Thomas G: PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization. Cell 1998;94:205–216.
  62. Press B, Feng Y, Hoflack B, Wandinger-Ness A: Mutant Rab7 causes the accumulation of cathepsin D and cation-independent mannose-6-phosphate receptor in an early endocytic compartment. J Cell Biol 1998;140:1075–1089.
  63. Pfeffer SR: Transport-vesicle targeting: Tethers before SNAREs. Nat Cell Biol 1999;1:E17–E22.

    External Resources

  64. Grabowski GA, Hopkin RJ: Enzyme therapy for lysosomal storage disease: Principles, practice, and prospects. Annu Rev Genomics Hum Genet 2003;4:403–436.
  65. Meikle PJ, Fuller M, Hopwood JJ: Mass spectrometry in the study of lysosomal storage disorders. Cell Mol Biol 2003;49:769–777.
  66. Pshezhetsky AV, Ashmarina M: Lysosomal multienzyme complex: Biochemistry, genetics, and molecular pathophysiology. Prog Nucleic Acid Res Mol Biol 2001;69:81–114.
  67. Strehle EM: Sialic acid storage disease and related disorders. Genet Test 2003;7:113–121.
  68. Callahan JW: Molecular basis of GM1 gangliosidosis and Morquio disease, type B. Structure-function studies of lysosomal beta-galactosidase and the non-lysosomal beta-galactosi dase-like protein. Biochim Biophys Acta 1999;1455:85–103.
  69. Hiraiwa M: Cathepsin A/protective protein: An unusual lysosomal multifunctional protein. Cell Mol Life Sci 1999;56:894–907.
  70. Pshezhetsky AV, Potier M: Association of N-acetylgalactosamine-6-sulfate sulfatase with the multienzyme lysosomal complex of beta-galactosidase, cathepsin A, and neuraminidase. Possible implication for intralysosomal catabolism of keratan sulfate. J Biol Chem 1996;271:28359–28365.
  71. Dell’Angelica EC, Mullins C, Caplan S, Bonifacino JS: Lysosome-related organelles. FASEB J 2000;14:1265–1278.
  72. Kjeldsen L, Calafat J, Borregaard N: Giant granules of neutrophils in Chediak-Higashi syndrome are derived from azurophil granules but not from specific and gelatinase granules. J Leukoc Biol 1998;64:72–77.
  73. Singh I: Biochemistry of peroxisomes in health and disease. Mol Cell Biochem 1997;167:1–29.
  74. Dansen TB, Wirtz KW: The peroxisome in oxidative stress. IUBMB Life 2001;51:223–230.
  75. Baumgartner MR, Saudubray JM: Peroxisomal disorders. Semin Neonatol 2002;7:85–94.
  76. Gartner J: Organelle disease: Peroxisomal disorders. Eur J Pediatr 2000;159(Suppl 3):S236–S239.

    External Resources

  77. Lazarow PB: Peroxisome biogenesis: Advances and conundrums. Curr Opin Cell Biol 2003;15:489–497.
  78. Brown LA, Baker A: Peroxisome biogenesis and the role of protein import. J Cell Mol Med 2003;7:388–400.
  79. Vizeacoumar FJ, Torres-Guzman JC, Bouard D, Aitchison JD, Rachubinski RA: Pex30p, Pex31p and Pex32p form a family of peroxisomal integral membrane proteins regulating peroxisome size and number in Saccharomyces cervisiae. Mol Biol Cell 2004;15:665–677.
  80. Eckert JH, Erdmann R: Peroxisome biogenesis. Rev Physiol Biochem Pharmacol 2003;147:75–121.
  81. Subramani S: Convergence of model systems for peroxisome biogenesis. Curr Opin Cell Biol 1996;8:513–518.
  82. Suzuki Y, Shimozawa N, Imamura A, Fukuda S, Zhang Z, Orii T, Kondo N: Clinical, biochemical and genetic aspects and neuronal migration in peroxisome biogenesis disorders. J Inherit Metab Dis 2001;24:151–165.
  83. Birschman I, Stroobants A, van den Berg M, Schafer A, Rosenkranz K, Kunau WH, Tabak H: Pex15p of Saccharomyces cerevisiae provides a molecular basis for recruitment of the AAA peroxin Pex6p to peroxisomal membranes. Mol Biol Cell 2003;14:2226–2236.
  84. Purdue PE, Lazarow PB: Peroxisome biogenesis. Annu Rev Cell Dev Biol 2001;17:701–752.
  85. Li X, Baumgart E, Dong GX, Morrell JC, Jimenez-Sanchez G, Valle D, Smith KD, Gould SJ: PEX11alpha is required for peroxisome proliferation in response to 4-phenylbutyrate but is dispensable for peroxisome proliferator-activated receptor alpha-mediated peroxisome proliferation. Mol Cell Biol 2002;22:8226–8240.
  86. Gould SJ, Valle D: Peroxisome biogenesis disorders: Genetics and cell biology. Trends Genet 2000;16:340–345.
  87. Gootjes J, Mooijer PA, Dekker C, Barth PG, Poll-The BT, Waterham HR, Wanders RJ: Biochemical markers predicting survival in peroxisome biogenesis disorders. Neurology 2002;59:1746–1749.
  88. Preuss N, Brosius U, Biermanns M, Muntau AC, Conzelmann E, Gartner J: PEX1 mutations in complementation group 1 of Zellweger spectrum patients correlate with severity of disease. Pediatr Res 2002;51:706–714.
  89. Maxwell MA, Nelson PV, Chin SJ, Paton BC, Carey WF, Crane DI: A common PEX1 frameshift mutation in patients with disorders of peroxisome biogenesis correlates with the severe Zellweger syndrome phenotype. Hum Genet 1999;105:38–44.
  90. Purdue PE, Zhang JW, Skoneczny M, Lazarow PB: Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7, a homologue of the yeast PTS2 receptor. Nat Genet 1997;15:381–384.
  91. Purdue PE, Skoneczny M, Yang X, Zhang JW, Lazarow PB: Rhizomelic chondrodysplasia punctata, a peroxisomal biogenesis disorder caused by defects in Pex7p, a peroxisomal protein import receptor: A minireview. Neurochem Res1999;24:581–586.
  92. Danpure CJ: Primary hyperoxaluria; in Scriver CR, et al (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 2001, pp 3323–3367.

 goto top of outline Author Contacts

Dr. Gursev S. Dhaunsi
Department of Pediatrics, Faculty of Medicine, Kuwait University
PO Box 24923
13110 Safat (Kuwait)
Tel. +965 531 9486, Fax +965 533 8940, E-Mail dhaunsig@hsc.edu.kw


 goto top of outline Article Information

Received: June 2, 2004
Revised: December 21, 2004
Published online: July 09, 2008
Number of Print Pages : 9
Number of Figures : 0, Number of Tables : 1, Number of References : 92


 goto top of outline Publication Details

Medical Principles and Practice (International Journal of the Kuwait University Health Sciences Centre)

Vol. 14, No. Suppl. 1, Year 2005 (Cover Date: Released July 2005)

Journal Editor: Al Awadi, F. (Kuwait)
ISSN: 1011–7571 (Print), eISSN: 1423–0151 (Online)

For additional information: http://www.karger.com/mpp


Open Access License / Drug Dosage / Disclaimer

Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.